Drug disposition and drug hypersensitivity.
About: This article is published in Biochemical Pharmacology.The article was published on 1987-03-01. It has received 197 citations till now.
Citations
More filters
TL;DR: Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions and cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients.
Abstract: Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy.
660 citations
TL;DR: Acyl glucuronides Revisited: Is the Glucuronidation Proces a Toxification as well as a Detoxification Mechanism? Drug Metabolism Reviews: Vol. 24, No. 1, pp. 5-47 as mentioned in this paper.
Abstract: (1992). Acyl Glucuronides Revisited: Is the Glucuronidation Proces a Toxification as Well as a Detoxification Mechanism? Drug Metabolism Reviews: Vol. 24, No. 1, pp. 5-47.
394 citations
TL;DR: The current status of adverse drug reactions is reviewed, briefly describing the complexity of the more bizarre reactions and outlining a strategy to eliminate serious adversedrug reactions.
Abstract: An adverse drug reaction is any undesirable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use. In contrast, an adverse drug event is an untoward occurrence after exposure to a drug that is not necessarily caused by the drug.1
When a drug is marketed little is known about its safety in clinical use because only about 1500 patients are likely to have been exposed to it.1,2 Thus drug safety assessment should be considered an integral part of everyday clinical practice since detection and diagnosis often depend on clinical acumen.
In this article we review the current status of adverse drug reactions, briefly describing the complexity of the more bizarre reactions and outlining a strategy to eliminate serious adverse drug reactions.
Summary points
Adverse drug reactions are a common clinical problem
They are diagnosed on clinical grounds from the temporal relation between the start and finish of drug treatment and the onset and offset of the reaction
Pharmacological adverse reactions are generally dose-dependent, related to the pharmacokinetic properties of the drug, and resolve when the dose is reduced
Idiosyncratic adverse reactions are not related to the known pharmacology of the drug, do not show any simple dose-response relation, and resolve only when treatment is discontinued
Vigilance by clinicians in detecting, diagnosing, and reporting adverse reactions is important for continued drug safety monitoring
370 citations
TL;DR: Accumulated clinical evidence points to drugs as the most important, if not the only, cause of toxic epidermal necrolysis.
Abstract: Toxic epidermal necrolysis is perhaps the most formidable disease encountered by dermatologists. Uncommon but not rare, toxic epidermal necrolysis occurs in 60 to 70 persons per year in France. It remains as puzzling a disorder as it was 34 years ago, when described by Lyell. Whether or not toxic epidermal necrolysis is the most severe form of erythema multiforme is still the subject of discussion. The physiopathologic events that lead to this rapidly extensive necrosis of the epidermis are not understood. Indirect evidence suggests a hypersensitivity reaction, but the search for potential immunologic mechanisms has resulted in little data to support this hypothesis. Accumulated clinical evidence points to drugs as the most important, if not the only, cause of toxic epidermal necrolysis. Sulfonamides, especially long-acting forms, anticonvulsants, nonsteroidal anti-inflammatory agents, and certain antibiotics are associated with most cases of toxic epidermal necrolysis. Many other drugs have been implicated in isolated case reports. All organs may be involved either by the same process of destruction of the epithelium as observed in the epidermis or by the same systemic consequences of "acute skin failure" as seen in patients with widespread burns. Sepsis is the most important complication and cause of death. Approximately 20% to 30% of all patients with toxic epidermal necrolysis die. Elderly patients and patients with extensive lesions have a higher mortality rate. Surviving patients completely heal in 3 to 4 weeks, but up to 50% will have residual, potentially disabling ocular lesions. The prognosis is improved by adequate therapy, as provided in burn units, that is, aggressive fluid replacement, nutritional support, and a coherent antibacterial policy. Corticosteroids, advocated by some in high doses to halt the "hypersensitivity" process, have been shown in several studies to be detrimental and should be avoided.
356 citations
TL;DR: Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only.
Abstract: Idiosyncratic drug reactions may be defined as adverse effects that cannot be explained by the known mechanisms of action of the offending agent, do not occur at any dose in most patients, and develop mostly unpredictably in susceptible individuals only. These reactions are generally thought to account for up to 10% of all adverse drug reactions, but their frequency may be higher depending on the definition adopted. Idiosyncratic reactions are a major source of concern because they encompass most life-threatening effects of antiepileptic drugs (AEDs), as well as many other reactions requiring discontinuation of treatment. Based on the underlying mechanisms, idiosyncratic reactions can be differentiated into (1) immune-mediated hypersensitivity reactions, which may range from benign skin rashes to serious conditions such as drug-related rash with eosinophilia and systemic symptoms; (2) reactions involving unusual nonimmune-mediated individual susceptibility, often related to abnormal production or defective detoxification of reactive cytotoxic metabolites (as in valproate-induced liver toxicity); and (3) off-target pharmacology, whereby a drug interacts directly with a system other than that for which it is intended, an example being some types of AED-induced dyskinesias. Although no AED is free from the potential of inducing idiosyncratic reactions, the magnitude of risk and the most common manifestations vary from one drug to another, a consideration that impacts on treatment choices. Serious consequences of idiosyncratic reactions can be minimized by knowledge of risk factors, avoidance of specific AEDs in subpopulations at risk, cautious dose titration, and careful monitoring of clinical response.
326 citations
Cites background from "Drug disposition and drug hypersens..."
...Alternatively, electrophilic metabolites can react with nucleophilic groups on proteins without covalent binding (Park et al., 1987)....
[...]
References
More filters
Journal Article•
1,495 citations
TL;DR: Experiments on the sensitization of guinea pigs with simple chemical compounds are described, with positive effects obtained by the administration of small quantities with 1:2:4 chlorodinitrobenzene, p-nitrosodimethylaniline, and a number of other aromatic compounds.
Abstract: Experiments on the sensitization of guinea pigs with simple chemical compounds are described. Positive effects were obtained by the administration of small quantities, namely fractions of milligrams, with 1:2:4 chlorodinitrobenzene, p-nitrosodimethylaniline, 1:2:4 trinitrobenzene, picryl chloride, four dichlorodinitrobenzenes, and a number of other aromatic compounds. Several substances chemically similar to those enumerated gave negative results. The first named compound is known to produce hypersensitiveness in human beings, a large number of cases having been observed in factory workers. The mechanism of these effects is discussed.
645 citations
TL;DR: Renal biopsies were performed on 13 patients treated with captopril and findings indicated an early stage of membranous glomerulopathy (MGP), which may be associated with the development of immune-complex glomerULopathy.
293 citations
TL;DR: Control studies using serum from subjects repeatedly exposed to halothane without the development of liver damage, and from patients with viral and toxic liver injury have confirmed the specificity of these findings to serve Halothane-associated liver injury.
Abstract: Circulating antibodies reacting specifically with the cell membrane of hepatocytes isolated from halothane-anesthetized rabbits were detected in nine of 11 patients with fulminant hepatic failure after helothane-induced anesthesia. The immunoglobulin deposition, as revealed by immunofluorescence, showed a granular pattern on the hepatocyte surface membrane. Preincubation of halothane-pretreated, but not of control, hepatocytes with serum containing this antibody rendered them susceptible to cytotoxic effects of normal lymphocytes in vitro. Control studies using serum from subjects repeatedly exposed to halothane without the development of liver damage, and from patients with viral and toxic liver injury have confirmed the specificity of these findings to serve halothane-associated liver injury. These results provide further evidence of an immunologic component in this condition.
264 citations
TL;DR: In this paper, the role of metabolic activation in Chemical-Induced Lung Injury was discussed and a detailed review of the biochemical mechanism of lung injury was presented. But this paper focused on lung injury.
Abstract: (1980). Biochemical Mechanisms in Chemical-Induced Lung Injury: Roles of Metabolic Activation. CRC Critical Reviews in Toxicology: Vol. 7, No. 2, pp. 103-176.
239 citations